Developing Image-Guided Histotripsy for the Non-Invasive Treatment of Osteosarcoma

Abstract

Osteosarcoma (OS) is the most common primary bone tumor in humans and in dogs, with a high level of biological, clinical, and genetic similarity between the canine and pediatric diseases. As such, canine OS is an excellent model in which to evaluate novel therapies for both human and veterinary OS, where new therapeutics are desperately needed. Functional outcomes and overall survival remains poor in both species despite definitive treatment, with no improvements in decades since the addition of chemotherapy to treatment regimens. Histotripsy is an emerging ablation modality with the potential to address this problem, as the first non-invasive, non-thermal, non-ionizing, and image-guided ablation technique. Histotripsy uses ultra-short, high-pressure focused ultrasound pulses to mechanically disintegrate target tissue via acoustic cavitation and has also been shown to induce immunostimulatory changes in the tumor microenvironment. Histotripsy has shown early promise for the treatment of OS in ex vivo canine samples and in treating small portions of canine OS tumors in vivo, followed by limb amputation. However, additional work is needed to optimize histotripsy for the complete ablation of OS, with a focus on the need for improved imaging in bone tumors and more preclinical work to translate this technology for dogs and humans with OS. This dissertation furthers the development of image-guided histotripsy for the treatment of OS, using a combination of canine and murine models of OS for maximum translational relevance. The research described herein (1) devises improved imaging and treatment strategies for the complete ablation of canine OS in vivo, (2) investigates ex vivo and preclinical characteristics of histotripsy for OS to improve therapeutic safety and efficacy, and (3) applies histotripsy in combination with immunotherapy for the first time in a clinical setting. The completion of this dissertation will significantly advance our technical capabilities and clinical understanding of histotripsy for OS. Future work will build upon this, focusing on investigating the immune outcomes of the described work and advancing patient-specific treatment paradigms, for the purpose of translating histotripsy into the clinic as a non-invasive, limb-sparing therapy for OS in dogs and humans.